1. Field of the Invention:
The present invention relates to the field of excitatory amino acid (EAA) receptor antagonists, and particularly to novel methods and compounds for blocking one or more EAA receptors.
2. Description of the Prior Art:
Excitatory amino acid receptors form a basic link for neurotransmission EAA receptors are of two general types, "ionotropic" and "metabotropic". Ionotropic receptors are directly coupled to the opening of cation channels in the cell membrane. There are at least three subtypes of ionotropic EAA receptors, namely those which are selectively activated by the agonists N methy-D-aspartic acid (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) and kainic acid (KA). Compounds that act as antagonists at the NMDA receptor complex can include compounds that act at the glutamate recognition site, the glycine recognition site, and the ion-channel binding site A G-protein or second messenger-linked "metahotropic" EAA receptor leads to enhanced phosphoinositide hydrolysis in the postsynaptic cell when activated by the agonists quisqualate, ibotenate or trans-1-aminocyclopentane-1,3-dicarboxylic acid.
Endogenous EAA receptor agonists include a number of substances that are found in the brain and spinal cord. The substances are all acidic amino acids, and include L-glutamic acid, L-aspartic acid, L-cysteic acid, L-homocysteic acid, L-cysteinesulfinic acid, L-homocysteinesulfinic acid, and quinolinic acid. Of these compounds, there is overwhelming evidence that L-glutamic acid and L aspartic acid mediate excitatory synaptic transmission at a substantial portion of all synapses throughout the central nervous system (CNS).
A number of selective, potent and bioavailable antagonists for excitatory amino acid receptors in the CNS have been discovered. A large body of data now shows that these agents are neuroprotective in animal models and may have therapeutic potential in the treatment of neurological disorders such as epilepsy, stroke, brain and spinal cord trauma, cerebral ischaemia, muscular spasms, neurodegenerative diseases and conditions including Huntington's chorea and dementia of the Alzheimer's type, Parkinson's disease, and Amyotrophic lateral sclerosis, anxiety, urinary incontinence, analgesia, muscle spasms, opiate tolerance and withdrawal, and as an antipsychotic. There remains a substantial need for the identification of new EAA receptor antagonists.
A variety of excitatory amino acid receptor antagonists have been identified in recent patents. In U.S. Pat. No. 4,902,687, issued Feb. 20, 1990 to Ornstein, there are described certain piperazine compounds useful as EAA receptor antagonists. The use of decahydroisoquinolines and piperidines, both of which may have tetrazole substitution, is described in U.S. Pat. Nos. 4,902,695 and 4,968,678, issued to Ornstein on Feb. 20, 1990 and Nov. 6, 1990, respectively. The use of heterocyclic dihydroxyquinoxaline and quinoxalinedione compounds as glutamate receptor antagonists for treating epilepsy, psychosis and dementia is described in European Patent Applications A1 348 872 and A2 315 959, respectively.
In U.S. Pat. No. 4,713,383, issued to Francis et al. on Dec. 15, 1987, there are disclosed certain [1,2,4]triazolo[1,5-c]quinazoline compounds which include a double-bonded moiety at the C5 position. Compounds with an oxygen or sulfur at this position are indicated to be useful as benzodiazepine antagonists; those with an imino group are indicated to be adenosine antagonists. Activity of the triazoloquinazolin-5-amines and -5-imines as adenosine antagonists is discussed in "Structure-Activity Profile of a Series of Novel Triazoloquinazoline Adenosine Antagonists", by Francis et al., in J. Med. Chem., v. 31, pp. 1014-1020 (1988). Similarly, the activity of certain triazoloquinoxalin-4-amines is presented in "[1,2,4]Triazolo[4,3-a]quinoxalin-4-amines: A New Class of A.sub.1 Receptor Selective Adenosine Antagonists", by Trivedi et al., in J. Med. Chem., v. 31, pp. 1011-1014 (1988). See also, "Adenosine Antagonists", by Michael Williams, in Medicinal Research Reviews, v. 9, no. 2, pp 219-243 (1989).
Triazoloquinoxalin-4-ones are described in U.S. Pat. No. 4,354,027, issued to Loev et al. on Oct. 12, 1982, as being useful as anti-hypertensive agents. Use of the triazoloquinoxaline-diones is described in "1,2,4-Triazolo[4,3-a]quinoxaline-1,4-diones as Antiallergic Agents", by Loev, et al., in J. Med. Chem., v. 28, pp. 363-366 (1985). The use of [1,2,4]Triazolo[4,3-a]quinoxalin-4(5H)-ones as antidepressants and antifatique agents is described in European Patent Application EP 107455 Al, filed May 2, 1984.